Drug dependence is linked to decreased volume of limbic-related structures, altered hippocampal morphology, and limbic- and hippocampal-related symptoms, such as deficits in learning and memory. Conversely, the hippocampus is involved in drug reward and relapse to drug seeking. Clarification of the time course, extent, and cause of drug-induced hippocampal neuroadaptations and identification of how hippocampal neuroadaptations impact addictive behaviors will greatly improve our understanding and treatment of addiction. A notable aspect of the hippocampus is its ability to generate new neurons throughout life. Adult-generated neurons are functionally integrated into hippocampal circuitry, and appear to be involved in hippocampal- dependent learning. Drugs of abuse, including morphine, decrease neurogenesis in the subgranular zone (SGZ) of the hippocampal dentate gyrus. This raises the possibility that opiate-induced alteration in neurogenesis leads to cognitive deficits, continued drug taking or relapse, or otherwise impedes recovery. We will test this possibility using state-of-the-art techniques to overcome obstacles in SGZ precursor analysis and thus advance our understanding of the relationship between opiate and hippocampal neurogenesis. Aim 1. Determine how morphine self-administration and withdrawal alter discrete stages of adult hippocampal neurogenesis. Chronic, but not acute, opiates decrease the birth of new cells and generation of neurons in adult hippocampus. Using morphine self-administration, here we will take the next essential step in understanding this action: delineate the precise effects of opiates and withdrawal on all cellular stages, from proliferation of stem and precursor cells, to maturation of young neurons, and eventual survival to maturity. Aim 2. Assess how altered adult hippocampal neurogenesis relates to drug seeking. Guided by Aim 1 and our preliminary data on the importance of new neurons to drug seeking after withdrawal, we will explore how voluntary running and hippocampal-dependent learning are altered by opiate exposure, and how running and learning influence drug-seeking and opiate-induced alterations in hippocampal neurogenesis. Aim 3. Evaluate the involvement of adult-generated hippocampal neurons in drug/context association. It is unknown if adult-generated neurons are influenced by or important in the drug/context association critical for reinstatement to self-administration or conditioned place preference (CPP). Using our novel transgenic mouse models to inducibly and selectively reduce hippocampal neurogenesis, we will examine the hypothesis that adult-generated neurons are activated by drug/context associations during a critical maturation window. These studies may indicate therapeutic approaches for treating opiate addiction or preventing opiate relapse. These studies will also improve our understanding of the complex mechanisms by which opiates affect brain function hippocampal function, and will provide insight into the role of the hippocampus and adult neurogenesis in addictive processes, a critical issue for addiction research in particular and biomedical science in general. Drug addiction is a devastating disorder marked by compulsive drug use, high propensity to relapse to drug taking, and cognitive deficits. Drugs of abuse, including heroin, lead to a decrease in the number of new neurons in the hippocampus, a brain region important for learning and memory. We will explore the potentially reciprocal relationship between opiate addiction and adult hippocampal neurogenesis, thus providing much- needed insight into the structure and function of the addicted brain as well as the function of new neurons in the adult brain.